The major goals of this proposal are 1) to confirm preliminary observations regarding the widespread nature of DNA hypomethylation in individuals who have colorectal adenomas; 2) to determine whether daily supplementation with pharmacologic doses of folic acid may attenuate or reverse either DNA hypomethylation or a more conventionally-accepted intermediary marker of colorectal cancer, the proliferation of the rectosigmoid mucosa; 3) to determine whether such supplementation can be provided without a significant incidence of side effects; and 4) to examine whether any beneficial effects of folic acid supplementation on these intermediary markers persist for up to one year after discontinuation of the vitamin. Colorectal cancer is the second most common cause of cancer death in the United States and in most of the developed world. Despite the remarkable advances in therapeutic modalities over the past five decades, the age- adjusted death rate from this cancer has remained essentially unchanged. Colonoscopic screening of individuals who are at enhanced risk of the disease may reduce mortality, but at an extraordinary financial cost to society. Furthermore, this approach does not remove the underlying disposition towards colonic carcinogenesis. A search for an effective and safe chemopreventive agent is therefore warranted. Epidemiologic studies and animal experiments indicate an inverse relationship between dietary intake of the vitamin folate and the risk of developing colorectal dysplasia and cancer. Furthermore, preliminary evidence in individuals who harbor colorectal adenomas indicates that DNA hypomethylation, a biochemical phenomenon which is uniformly observed in colorectal neoplasms and which may play a causative role in carcinogenesis, is present systemically and as a widespread lesion in the colorectal mucosa, and that supplementation with pharmacologic doses of folic acid may reverse these abnormalities. The study design is a prospective, double-blind, placebo-controlled, multi-center trial. It will be conducted with the full cooperation of the Eastern Collaborative Oncology Group (ECOG), a large and well-established consortium of medical centers that has an excellent record for the successful conduct of large clinical trials. Subjects who have recently had colonoscopic resection of adenomas will be randomized to receive either 5 mg. tablets of folic acid daily or a placebo for one year. Repeat colonoscopy at 6 months, 1 year, and 2 years will be performed to monitor the intermediary markers. Alterations in mucosal proliferation and DNA hypomethylation which occur in response to folate intervention will be compared, providing a means of determining whether the measurement of DNA methylation parallels the response seen in more conventionally-accepted intermediary markers. The results of this trial will be used to determine whether a larger and longer Phase III trial is warranted, in which the endpoints will consist of adenoma and cancer occurrence.